New 1,1’-Biphenyl-4-sulfonamides as Potent and Selective Human Carbonic Anhydrase Inhibitors

Carbonic anhydrases (CAs) are an attractive and versatile target for the development of new agents active in different diseases. The different isoforms of this metalloenzyme are involved in key physiological processes, so that there is growing interest in the design of new CA inhibitors. We have developed a first series 1,1’-biphenylsulfonamides as human CA (hCA) inhibitors [1], evaluating their activity in hCA isoforms I, II, IX and XIV, using acetazolamide (AAZ) as reference compound. These compounds are characterized by a sulfonamide group, a substituent which, in its anionic form, can coordinate the zinc atom in the catalytic site. Most of the derivatives inhibited all the isoform, with Ki values in the nanomolar range of concentration, outperforming AAZ. In particular, the major activity is on the XIV isoform, involved in epilepsy and retinopathies. X-ray crystallography and molecular modelling studies on the adduct of these derivatives with the different hCAs provided insights into the molecular determinants responsible for its high affinity toward the target enzyme. Pursuing our studies on hCA inhibitors, we designed new 4’-substituted 1,1’-biphenyl-4-sulfonamides [2], moving the amino or carboxyphenyl unit from 4” to 3” or 2” position. This shift results in a substantial change in the inhibitory activity: it moves selectivity towards hCAII with Ki values in the subnanonmolar range, which is involved in the onset of glaucoma, and it causes a drop of activity against hCAIX. The reported new compounds have potential as novel therapeutic agents. In fact, a small change in the structure leads to a selectivity towards different isoforms, each one involved in specific pathologies such as glaucoma, epilepsy, cerebral edema and some types of tumors. [1]: La Regina G et al. (2015). J. Med. Chem 58 (21): 8564-8572. [2]: La Regina G et al. (2020). ACS Med. Chem. Lett. 11 (5): 633-637.